Background: Thyroid cancer: The incidence of thyroid cancer has doubled over the last two decades. Although most patients with thyroid cancer of follicular cell origin have an excellent prognosis, 10% - 15% will have refractory disease to conventional therapy (resection combined with radioiodine ablation and thyroid hormone for TSH suppression). Chemotherapy and external beam radiation are ineffective in patients with metastatic disease. The overall 10 year survival of patients with metastatic thyroid cancer of follicular cell origin is approximately 40-50%. Adrenocortical carcinoma: Approximately two-thirds of patients who present with adrenocortical carcinoma have locoregional disease and metastasis. Unfortunately, despite combined multimodality therapy, the overall prognosis of patients with adrenocortical carcinoma remains dismal, with a 5-year survival of less than 35%.Summary:We are making progress towards identifying molecular targets and novel agents for endocrine cancers. We have developed two novel approaches of evaluating response to therapy in our in vivo studies. In transgenic mouse model of thyroid cancer, we have been able to quantitatively measure tumors by high-resolution ultrasound and demonstrated excellent correlation between gross post-mortem tumor measurements and thyroid ultrasound measurements. In another model of lung metastasis of cancer cell lines stably transfect with a luciferase reporter, we are able to image sites of metastasis with a quantifiable measurement of luciferase activity (tumor volume) with correlates with tumor burden. Such approaches for assessing tumor response have several advantages including 1) real time assessment of tumor response to therapy, and 2) determining the natural history of therapy withdrawal of agents inducing tumor regression as mice are not sacrificed to evaluate response.From our genome-wide expression analysis, we have identified genes which are druggable targets and altered in most cancers (e.g. overexpression of TOP2A in 100% of adrenocortical carcinoma samples analyzed). Furthermore, we have integrated our data from our quantitative high throughput screening of compounds which showed anticancer activity in cell lines with the genomic data from human tumor samples. This has resulted in identifying several classes of drugs with preferentially high anticancer activity (80% of drugs in class) in certain types of tumors (e.g. topoisomerase inhibitors in adrenocortical carcinoma). We are currently validating the anticancer activity of these compounds in vivo and hope to translate these findings into clinical trials for patients with advance thyroid cancer and adrenocortical carcinoma.